In recent years, a number of peptides were found that were suitable for various pharmaceutical agent applications. In most cases, however, peptides cannot be taken orally, since they are often already metabolized or in turn are very quickly excreted from the body before reaching the site of action.
Peptidomimetic agents are peptide-like structures that can imitate or inhibit peptide actions as ligands. They are distinguished by a higher stability, by which the probability increases of reaching the site of action and exerting there an action as a pharmaceutical agent.
Aggregates that consist of incorrectly folded proteins very frequently occur in the course of neurodegenerative diseases. In the case of Alzheimer's disease, the extracellular deposits that are known as “plaques” from the literature, which mainly consist of β-amyloid, represent a main feature. The neurofibrillary bundles that occur intracellularly and mainly consist of hyperphosphorylated Tau protein are another feature.
The investigation of β-amyloid plaque as well as the combatting of the same has occupied a central role in the research of Alzheimer's disease in recent years.
At this time, no treatment that acts on the causes of disease is available for treating Alzheimer's disease, Parkinson's disease, Lewy Body dementia or other neurodegenerative diseases. The drug target that is best known and best developed at this time for treating Alzheimer's disease deals with the β-amyloid-induced development of plaque. Alzheimer's disease affects 15 million humans in Europe and in the U.S.A. The incidence is 1-2% and increases to about 4% in the ninth decade of life.
The deposits in the form of plaque mainly consist of amyloidogenic β-amyloid. This amyloidogenic molecule species is formed by processing the amyloid-precursor protein (APP) (Kang et al., Nature, 325 (6106): 733-6, 1987; Goldgaber et al., J Neural Transm Suppl. 24: 23-28, 1987). APP, a transmembrane protein, whose physiological function is still not completely clarified (Selkoe, J Alzheimer's Dis., 3(1): 75-80, 2001), is present everywhere in the organism, but primarily in neuronal cells.
During and after the transport of the APP by the secretory pathway, the protein can be cleaved in various ways (Goate et al., Nature, 349 (6311): 704-6, 1991). The corresponding proteolytic activities are named α-, β-, or γ-secretase. The activity of the α-secretase results in the cleavage of the soluble, extracellular portion of the protein (Esch et al., Science, 248 (4959): 1122-4, 1990). In this case, the transmembrane portion remains (non-amyloidogenic pathway). Another path of the processing contains the cleavage by β- and γ-secretase (amyloidogenic pathway). The cleavage by the β-secretase activity results in a somewhat smaller secreted fragment (β-APPs) and a larger transmembrane portion (C-99). The C-99 fragment is then cleaved by the γ-secretase activity within the transmembrane portion. The amyloidogenic Aβ-peptides with 40 or 42 amino acids (Aβ1-40, 1-42) result from this cleavage, which can be carried out primarily on two sites.
Aβ-1-42 has a strong tendency to form β-folded-sheet structures, which are almost impervious to degradation by natural means. β-Folded-sheet structures have a very strong tendency to form fibrils and ultimately turn into large aggregates.
In addition to the strong tendency toward aggregation, Aβ-1-42 is distinguished in particular by a pronounced toxicity. Among other things, the presence of Aβ1-42 leads to an increase of oxidative stress as well as increased lipid peroxidation (Butterfield, D. A., Free Radic Res. 2002 December; 36 (12): 1307-13).
Aβ1-42 disrupts the functionality of the synapses and results in excitotoxicity by a disruption of the cellular calcium balance. By the already mentioned lipid peroxidation, it results in the production of toxic oxidation products, which disrupt the functionality of ATPases, glutamate and glucose transporters (Mattson, M. P. and Chan S, L., Cell Calcium. 2003 October-November; 34 (4-5): 385-97). The result is a loss of nerve cells by necrosis or apoptosis.
A number of in-vivo and in-vitro models, which impressively confirm the role of Aβ1-42 in connection with neurodegeneration, exist. In transgenic mouse models, behavior deficits were also clearly attributable to Aβ31-42.
The U.S. Pat. No. 5,985,242 describes retroinverse sequences that consist of D-amino acids, derived from the amino acid range 17-21 of β-amyloid. The molecules described there influence the aggregation of β-amyloid.
WO-03/082906 A discloses peptides that are derived from N-terminal sequences of the β-synuclein and exert protective action relative to the neurotoxicity of β-amyloid.
The direct prevention of the aggregation behavior of β-amyloid by sequences that are directly derived from β-amyloid protein, as proposed in U.S. Pat. No. 5,985,242, involves the risk, however, of additional complications, since, as already known per se, small amyloid-like peptides can be directly neurotoxic. However, the inhibition of the neurotoxicity exerted by already aggregated Aβ1-42 (i.e., without explicit influence of the aggregation behavior) could even offer a great advantage. The peptides built up to form L-amino acids and described in WO 03/082906 A meet this requirement, but have a stability that is not quite optimum for use as pharmaceutical agents.